Recent technical advances in our laboratory make possible studies of the coronary microcirculation in the beating left ventricle of the cat. To study the microcirculation in the beating heart two major sources of movement, respiratory and cardiac, must be eliminated or compensated for in some way. To minimize respiratory-induced motion the animals are ventilated by high frequency jet ventilation. Secondly, arteriolar movement will be compensated for by visualizing the vessels with stroboscopic illumination synchronized to the cardiac cycle by a computer which makes the microvasculature appear to be stationary. Microvascular diameters can be measured or pressures can be obtained with a computer controlled pipette micromanipulator and the servonull technique. Using these techniques preliminary studies with 5-hydroxytryptamine have demonstrated that arterioles greater than 100 millimicron constrict while arterioles less than 100 millimicron dilate in response to the same stimulus. Vasopressin produces opposite effects: dilation of arterioles greater than 100 millimicron and constriction of arterioles less than 100 millimicron. This proposal will test the hypothesis that different segments of the coronary microcirculation will respond differently to a common stimulus. The specific questions to be examined in these studies are: 1) How does 5-hydroxytryptamine alter microvascular dynamics (pressure and diameter) in different segments of the coronary circulation? What are the mechanisms involved in these differential responses? 2) Is the distribution of microvascular resistance altered in a qualitatively different manner following vagal stimulation vs exogenously administered acetylcholine? 3) What is the interaction between vagal stimulation and the sympathetic nervous system in the response of the microcirculation? 4) What is the role of the endothelium in the segmental microvascular responses to humoral agents? and, 5) How does a pathophysiologic stimulus such as acute hypertension alter the microvascular response to humoral agents. These studies on the microcirculation may provide conceptually important information on the regulation of coronary vascular resistance at the microcirculatory level.